The human immunodeficiency virus type-i (HIV-i) is a complex retrovirus that encodes six regulatory proteins, including Tat. The Tat protein is a potent transcriptional activator of the HIV-1 long terminal repeat promoter element. A regulatory element between +1 and +60 in the HIV-1`long terminal repeat which is capable of forming a stable stem-loop structure, designated TAR, is critical for Tat function. In the absence of Tat, RNA polymerase II (pol II) terminates transcription prematurely. Tat-TAR interactions help convert pol II interactions with the RNA template into efficiently produced full-length viral transcripts. We have recently demonstrated that combinatorial libraries composed of tripeptides contained molecules that not only bound to TAR but also inhibited Tat interaction with Tar and subsequent LTR directed transcription was reduced in cell culture. The goal of the proposed research is the discovery of low molecular weight non-peptide compounds that inhibit HIV replication by binding to the TAR RNA element. The success of this research would open the door to new opportunities in the discovery of drugs which bind to discrete RNA structures with possible applications for diseases such as cancer and aids. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE